T-cell-mediated immunodeficiency caused by anti-interferon-γ autoantibodies promotes the pathogenesis of Talaromycosis marneffei

Anti-interferon-γ autoantibody (AIGA)-associated adult-onset immunodeficiency is an important underlying condition in patients with severe talaromycosis caused by Talaromyces marneffei , but the mechanisms underlying impaired antifungal immunity remain incompletely understood. This study aimed to define the contributions of CD4⁺ T cells, CD8⁺ T cells, and IFN-γ-dependent immune signaling to host defense against T. marneffei . We used an intranasal BALB/c mouse infection model with antibody-mediated CD4⁺ T-cell depletion, CD8⁺ T-cell depletion, or IFN-γ neutralization, together with immunological assays using sera from AIGA-positive patients and healthy controls. In mice, T. marneffei infection induced stronger and more sustained T-cell activation in the lungs than in the spleen, with pulmonary CD4⁺ T-cell activation representing the predominant response and CD8⁺ T cells showing distinct temporal kinetics. Depletion of CD4⁺ or CD8⁺ T cells, or blockade of IFN-γ, impaired body-weight recovery and reduced survival, aggravated pulmonary and splenic injury, and delayed fungal clearance. In clinical immunological assays involving 28 AIGA-positive patients and 30 healthy controls, depletion of IgG from AIGA-positive sera restored IFN-γ⁺TNF-α⁺ CD4⁺ and CD8⁺ T-cell responses toward healthy-control levels, suggesting that patient IgG suppresses T-cell cytokine responses. AIGA-positive sera contained IgG that bound IFN-γ and attenuated IFN-γ-induced STAT1 phosphorylation and HLA-DR upregulation in THP-1 cells, supporting functional neutralization of IFN-γ signaling and impaired antigen-presenting cell activation. Together, these findings indicate that AIGA-associated talaromycosis involves impaired IFN-γ-dependent coordination of innate effector functions and T-cell responses. Clinically, they support consideration of AIGA-associated adult-onset immunodeficiency in HIV-negative patients with severe or disseminated talaromycosis, particularly in endemic regions, and provide a rationale for future studies aimed at restoring IFN-γ bioactivity.